tbuckley/cabot-search huggingface dataset:
QOL-03. PATIENT-PARTNER RELATIONSHIPS AND QUALITY OF LIFE IN BRAIN TUMOR PATIENT
Authors: Maria Boccia, Ekokobe Fonkem, Nick Frye, Jennifer Murillo, Elizabeth Anyanda, Adam Tamimi, Eva Bradshaw
Journal: Neuro-Oncology (2023)

Abstract As cancer treatment has advanced, quality of life (QoL) has become a significant consideration in patient and survivor care. The 2005 Institute of Medicine Cancer Survivorship Care Planning guide requires the inclusion of information on the possible effects of cancer on relationship satisfaction and sexual functioning associated with QoL. Guided by the cognitive-transactional model of chronic illness, this study explored the extent to which relationship satisfaction and sexual dysfunction was associated with QoL. Thirty patients and their partners were recruited from a neuro-oncology practice and given a QoL questionnaire (FACT-Br) and measures of relationship satisfaction (Couple Satisfaction Index) and sexual functioning. Women were given the Female Sexual Function Index (FSFI). Men were given scales to assess premature ejaculation (PE), and erectile dysfunction (ED). In addition, information about site and type of tumor and treatment (surgery, radiation, chemotherapy) was collected. Descriptive statistics as well as T-tests and regression models were used to analyze the data. Relationship satisfaction varied across participants and was significantly related to QoL for patients. There was significant sexual dysfunction as was previously reported by our team. QoL and relationship satisfaction were correlated with sexual dysfunction. Our capacity to address the relationships of patients is dependent on our understanding the types of difficulties encountered. Specifically, partners are often also engaged in the role of primary caregiver, understanding these relationships and how to ensure their health can be critical for QoL and outcomes for brain tumor patients.
NCOG-29. THE NEURO-ONCOLOGY MAGNITUDE OF CLINICAL BENEFIT SCALE (NEURO-MCBS) AS A COMPREHENSIVE AND CLINICALLY RELEVANT ASSESSMENT TOOL TO DETERMINE CLINICAL BENEFIT FROM TARGETED THERAPIES IN CNS TUMORS
Authors: Sylvia C Kurz, Mirjam Renovanz, Johannes Rieger, Paula Bombach, Lucia Grosse, David Rieger, Svenja Hucker, Hanni Hille, Melina Hippler, Oeznur Oener, Kristina Ruhm, Janina Beha, Holly S Malek, Yvonne Moeller, Michael Bitzer, Nisar Malek, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Once first-line therapy options fail, there are no effective therapy options for most neuro-oncological conditions, including glioblastoma, gliomas, and brain metastases, thereby representing a high unmet clinical need. Novel targeted therapy options are often explored in small phase-I studies or are given as off-label therapies. Assessment of treatment efficacy in this setting is challenging and should incorporate outcome measures such as progression-free survival (PFS) or objective response rate (ORR) as well as clinical parameters. To address this, we developed the Neuro-Oncology Magnitude of Clinical Benefit Scale (Neuro-MCBS) as a comprehensive clinical tool to assess treatment efficacy in patients with CNS tumors who receive off-label targeted therapies outside of clinical trials. We prospectively evaluated the feasibility and clinical utility of the Neuro MCBS in a neuro-oncology patient cohort enrolled in MTB@ZPM. METHODS MTB@ZPM (NCT03503149) is a longitudinal observational study that provides comprehensive molecular profiling, consensus-guided and ranked targeted therapy recommendations and collection of prospective clinical outcome data. The Neuro-MCBS (grade 1 + 2=clinical benefit, grade 3=minimal benefit, grade 0=no benefit) was applied and correlated with PFS, the PFS2/PFS1 ratio, performance status (KPS, ECOG), and imaging parameters. RESULTS From February 1st, 2022 until January 31st, 2023, 70 patients were enrolled. While only a minority of n=17/36 (47%) glioblastoma and n=2/8 (25%) IDH-mutant astrocytoma patients benefited from targeted therapies, n=7/8 (88%) meningioma, n=9/10 (90%) brain metastases, and n=5/8 (63%) other tumor patients achieved a Neuro-MCBS of 1 or 2, i.e. derived clinical benefit from the molecularly based therapy. CONCLUSIONS The Neuro-MCBS is a comprehensive and clinically relevant assessment tool that incorporates clinical, imaging, and survival outcome data to determine the degree of clinical benefit from targeted therapies in patients with primary and secondary CNS tumors. Its incorporation into clinical practice provides an objective outcome measure of clinical utility vs. futility of targeted therapies.
IMMU-11. <i>NLRP3+</i> TUMOR-ASSOCIATED MYELOID CELLS ARE ENRICHED IN ASTROCYTIC GLIOMAS AND REPRESENT A THERAPEUTIC VULNERABILITY
Authors: Vidya Chandramohan, Kevin Stevenson, Yen-Rei Andrea Yu, Zachary Reitman, Yiping He, Roger McLendon, Cristina Osorio, Simon Gregory, Eric Lipp, Annick Desjardins, Allan Friedman, Smita Nair, Anoop Patel, Darell Bigner, David Ashley
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor-associated myeloid cells (TAMs) are known drivers of immunosuppression and glioma progression. Hence novel approaches for repolarizing TAMs from a protumorigenic to an antitumorigenic phenotype is an active area of investigation. While single-cell RNA sequencing (scRNA-seq) studies have characterized glioma TAMs in great detail, their uniqueness or similarity to TAMs in other tumors remains unknown. Cross-comparison of glioma TAMs with TAM subsets from other tumor types will aid in identifying novel TAM-targeted immunotherapies. METHODS We performed scRNA-seq of ~26K myeloid cells from nine patients with high-grade astrocytoma (n=3) and oligodendroglioma (n=6). The scRNA-seq findings were validated using TCGA RNA-seq data, public scRNA-Seq data, and immunohistochemistry (IHC) analysis. RESULTS The TAM clusters in gliomas predominantly exhibited a microglia-specific gene signature, while macrophage and monocyte clusters were also identified. Utilizing canonical TAM markers, we identified three major TAM subtypes, SPP1+ regulatory, FOLR2+ tissue-resident, and NLRP3+ inflammatory, enriched in astrocytomas. A gene set enrichment analysis of the three TAM subtype genes confirmed their enrichment in astrocytomas (IDHMut-non-codel) (P=0.0005; normalized enrichment score [NES]=1.79) in the TCGA bulk RNAseq data from IDH1-mutant LGGs. Investigation of the three TAM subtype markers in public scRNA-seq data confirmed their enrichment in immune/myeloid clusters across multiple glioma types (gangliogliomas, pilocytic astrocytomas, astrocytomas, diffuse midline gliomas, and glioblastomas). Finally, IHC analysis of 14 astrocytomas demonstrated regional variation in NLRP3 and FOLR2 expression in all cases, with a trend toward an inverse association between NLRP3 and FOLR2 expression. CONCLUSIONS 1) Astrocytomas (IDHMut-non-codel) comprise TAM subsets common across multiple tumor types. 2) The FOLR2+ TAMs predict favorable outcomes, while the NLRP3+ TAMs are immunosuppressive and predict adverse outcomes in breast cancer. Given the inverse expression of NLRP3 and FOLR2 in astrocytomas, we hypothesize that NLRP3 TAMs+ are immunosuppressive and a potential immunotherapeutic target in astrocytomas.
INNV-18. MULTIPHASE COMBINED TREATMENT, INCLUDING INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY FOR ADULTS WITH GBM: SINGLE INSTITUTE REAL WORLD MEDICAL DATA IN THE LIGHT OF CLINICAL TRIAL RESEARCH DATA
Authors: Stefaan Van Gool, Peter Van de Vliet, Linde Kampers, Jennifer Makalowski, Tobias Sprenger, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2023)

Abstract A phase III prospective externally controlled cohort trial recently demonstrated beneficial effects of DCVax®-L for adults with GBM. The beneficial effect of TTF was demonstrated in a RCT. We designed a multiphase combined treatment using subsequentially 1/ modulated electrohyperthermia and Newcastle Disease Virus therapy to induce immunogenic cell death (ICD) during temozolomide maintenance chemotherapy, 2/ two autologous DC vaccinations (IO-Vac®), and 3/ ICD immunotherapy, long-peptide vaccines and one boost IO-Vac® vaccine. During phase 2 + 3, individualized modulatory immunotherapy was provided. Fifty adults with first-line IDH1wt GBM were retrospectively analysed: MGMT promoter-unmethylated (unmeth, 10 f, 18 m); -methylated (meth, 12 f, 10 m). Median age was 48y, median Karnofsky performance index was 80. More than half of the patients had less than complete resection. Dynamics in tumor biology and immune response were demonstrated during treatment (e.g. mRNA expression for PDL1 in circulating tumor cells), and required treatment adaptations (checkpoint inhibitors). The median OS of unmeth and meth patients were 22m (2y-OS: 42%) resp. 38m (2y-OS: 81%, p=0.0414). There were no considerable treatment-related adverse reactions. The (external) control arms in the DCVax®-L and TTF trials, which reflect the current standard-of-care clinical results, showed median OS and 2y-OS of 15m/21% in unmeth and 21m/42% in meth patients. TTF improved the OS in both unmeth and meth patients (17m/27% and 32m/59%), while DCvax®-L improved OS only in meth patients (15m/19% and 30m/58%). These real world data support to prospectively explore the addition of individualized multimodal immunotherapy during and after standard of care, and the role of treatment adaptations during treatment.
DDDR-28. DNA DAMAGE SENSING KINASES ATR AND ATM-DEPENDENT PHOSPHORYLATION OF RRM2 PROMOTES PROTEIN STABILIZATION AND CHEMO-ADAPTATION
Authors: Graysen McManus, Ella Perrault, Cheol Park, Divya Ventrapragada, Shreya Budhiraja, Killian Buechler, Amelia Stepniak, Snehasis Mishra, Jason Miska, Atique Ahmed
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly heterogeneous, primary malignant brain tumor in adults that shows limited response to standard-of-care therapies, such as chemotherapy and radiation. This is due, in part, to the development of therapeutic resistance. To characterize the adaptive mechanisms GBM cells use to evade the standard chemotherapy, temozolomide (TMZ), single-cell RNA sequencing analysis was conducted on an in vivo patient-derived xenograft (PDX) model of GBM, before, during, and following TMZ-based therapy. Our data revealed 149 genes to be uniquely expressed in the during-TMZ condition (p&amp;lt; 0.0001), including the rate-limiting regulatory enzyme of dNTP metabolism, ribonucleotide reductase (RNR) enzyme. Network analysis of pathways enriched during therapy revealed an interaction between the (RNR) enzyme, RRM2, and DNA damage response genes in the ATM and ATR kinase-signaling pathways. RRM2-dependent deoxynucleotide (dNTP) production is required for DNA repair and cell survival following TMZ treatment. Therefore, we investigated whether ATR and ATM kinases directly interact with RRM2 to promote its stability. TMZ treatment triggered the activation of DNA damage response machinery and protein kinases, ATM, ATR, CHK1, and CHK2, which physically interacted with RRM2 across multiple GBM PDX cell lines. Co-IP and immunoblot analyses along with cycloheximide chase analysis showed increased phosphorylation of the threonine residue on RRM2 during therapy, preventing its degradation. As such, we hypothesize that early DNA damage sensing by ATM and ATR kinases, and their subsequent phosphorylation of RRM2, promotes the maintenance of purine nucleotide pools needed for DNA repair and development of chemo-resistance. This novel and targetable TMZ response axis presents a promising clinical opportunity for GBM therapy, using FDA-approved inhibitors of these targets to block the purine metabolic adaptations that drive resistance and sensitize GBM cells to TMZ therapy.
CSIG-16. PTEN LOSS IN GLIOMA CELL LINES FACILITATES IMMUNE EVASION BY UPREGULATING EXTRACELLULAR VESICLE BIOGENESIS AND PD-L1 CARGO
Authors: Julio Sanchez, Timothy Pierpont, Dariana Argueta-Zamora, Kristin Wilson, Avery August, Richard Cerione
Journal: Neuro-Oncology (2023)

Abstract Phosphatase and tensin homologue (PTEN) is deleted or mutated in over 50% of all glioblastoma (GBM) cases. Recently, PTEN loss has been implicated as a prognostic biomarker for patients likely to be non-responders treated with immune checkpoint inhibitor (ICI) therapy. Indeed, a growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1) and the development of an immunosuppressive tumor immune microenvironment (TIME), likely the result of an altered secretome. This raised the question of whether the loss of PTEN impacts the biogenesis and function of extracellular vesicles (EVs), given their functional contributions to immunosuppression and tumor growth. Here we show that glioma cell lines with no or reduced PTEN expression produce elevated numbers of EVs, as measured through nanoparticle tracking analysis. Pharmacological inhibition of PI3K reversed this observation, indicating that this phenomenon occurs in a PI3K-dependent manner. Moreover, we show through flow cytometry and immunoblot analysis that the ability for the inflammatory cytokine interferon-γ (IFN-γ) to upregulate PD-L1 at the cell surface and as EV-associated cargo is markedly increased in cells lacking PTEN. Lastly, we show that in response to IFN-γ, EVs derived from glioma cells lacking PTEN exhibit an enhanced ability to inhibit TCR signaling in a Jurkat reporter system. Taken together, these findings shed new light on how the loss of a major tumor suppressor, PTEN, can alter EV biogenesis and function and contribute to an immunosuppressive extracellular milieu. Future studies will be directed toward exploring whether loss of PTEN function alters additional EV-associated immuno-modulatory proteins relevant to other immune cell populations, toward gaining a further understanding of how EVs shape the “cold” TIME of GBM and the potential therapeutic benefit of combining PI3K inhibitors with ICIs.
EPID-20. SEX-SPECIFIC DIFFERENCES IN MENINGIOMA SUBTYPES AND MUTATIONS – A RETROSPECTIVE ANALYSIS
Authors: Natalie Berghaus, Thomas Hielscher, Abigail Suwala, Franziska Maria Ippen, Miriam Ratliff, Christel Herold-Mende, Wolfgang Wick, Andreas von Deimling, Felix Sahm
Journal: Neuro-Oncology (2023)

Abstract A variety of intrinsic and extrinsic factors are known to influence and promote the development of cancer. Although the patients’ gender can influence extrinsic factors, biological sex is an important intrinsic factor. Here, it must also be considered that hormone levels change over the lives of patients. To further investigate these aspects, meningioma can serve as a prototype tumor. Differences are already obvious when analyzing the epidemiology and outcomes: Females are more frequently diagnosed with meningioma, but high-grade meningiomas and fatal outcomes are more frequently observed in males. To further resolve sex and potentially hormone-specific differences, we retrospectively examined a dataset of 798 patients (females n=541, males n=257). Additionally, we arbitrarily set a cut-off of 58 years to stratify for females between pre- and post-menopause. The male cohort was analyzed accordingly to exclude an age-dependent effect. Further, the female cohort was subdivided into “45-55 years” and “other” to analyze the impact of high hormone fluctuations within menopause. When examining the histological data, we found that women displayed the chordoid subtype more frequently than men (6.3% vs. 1.6%). In the age-dependent analyses, there may be a signal for a hormone-dependent effect, as for females this subtype was diagnosed more frequently &amp;lt; 58 than &amp;gt; 58 years of age (10.6% vs. 1.9%; males: 0% vs. 3.0%) and within the menopause (15.5% vs. 3.2%). The same pattern was noted for the TRAF7 mutation, which was detected more frequently in females (20.2% vs. 7.7%), females &amp;lt; 58 years (23.9% vs. 15.6%, males: 6.2% vs. 9.1%) and females within the menopause (27.9% vs. 17.6%) than in the respective other subgroups. This preliminary data warrants further research in larger, comprehensively annotated cohorts and analysis for hormone levels and receptor expression.
SURG-04. FAST DETECTION OF GLIOMA INFILTRATION USING LABEL-FREE OPTICAL MICROSCOPY AND DEEP NEURAL NETWORKS
Authors: Akhil Kondepudi, Melike Pekmezci, Katie Scotford, Cheng Jiang, Asadur Chowdury, Xinhai Hou, Lin Wang, Wajd Al-Holou, Sandra Camelo-Piragua, Honglak Lee, Christian Freudiger, Mitchel Berger, Shawn Hervey-Jumper, Todd Hollon
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Fast and accurate detection of tumor infiltration is a central challenge in the comprehensive management of diffuse glioma patients. Despite our best real-time tumor detection strategies, such as intraoperative MRI and fluorescence-guided surgery, dense and safely resectable tumor infiltration remains at the surgical margin in over 85% of diffuse glioma patients. Patterns of treatment failure demonstrate that glioma recurrence occurs at the surgical margin in the majority of patients due to residual tumor burden. Objective Here, we present FastGlioma, an artificial intelligence (AI)-based intraoperative diagnostic system for fast (&amp;lt; 10 seconds) detection of diffuse glioma infiltration at microscopic resolution without the need for tumor-specific markers. Method FastGlioma is trained using large-scale, self-supervised visual feature learning on stimulated Raman histology (SRH), a rapid, label-free, optical microscopy technique, and a GPT-style whole slide SRH tumor infiltration scoring method. We pushed the performance limits of FastGlioma by investigating the trade-off between imaging speed versus accuracy for microscopic tumor detection. RESULTS In a large prospective external testing cohort of diffuse glioma patients (180 patients, 935 surgical margin specimens) who underwent intraoperative SRH imaging, we demonstrate that FastGlioma was able to detect and quantify microscopic tumor infiltration with an average AUROC of 92.1 +/- 0.0%, performing on par with three expert neuropathologists on the same task. FastGlioma is over 10X faster than previous SRH-based methods and 100X faster than conventional H&amp;E histology. Finally, we demonstrate that FastGlioma was &amp;gt; 20% more accurate at detecting dense tumor infiltration when compared to radiologic features or 5-aminolevulinic fluorescence (98.0% versus 77.8% accuracy) for both IDH-mutant diffuse gliomas and IDH-wildtype glioblastomas. CONCLUSION Our results demonstrate how intraoperative optical imaging and deep neural networks can achieve fast and accurate tumor detection, unlocking the role of AI in improving the surgical management of brain tumor patients.
EXTH-53. VEGFR2-SPECIFIC CAR-T CELLS SHOW IMPROVED TUMOR INFILTRATION IN SYNGENEIC MOUSE GLIOMA MODELS
Authors: Maximilian Mastall, Gina Dunkel, Manuela Silginer, Naoki Okada, Tobias Weiss, Michael Weller, Bettina Weigelin, Patrick Roth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Chimeric antigen receptor (CAR-)T cell therapy, a powerful immunotherapy against hematological malignancies, has so far limited efficiency in solid tumors. Also in glioblastoma, a major obstacle remains limited infiltration of CAR-T cells into the tumor. Vessel-targeting CAR-T cells have been shown to infiltrate solid tumors more efficiently. Vascular endothelial growth factor receptor 2 (VEGFR2) is expressed in the glioma vasculature and VEGFR2-specific CAR-T cells prolong the survival of xenograft glioma-bearing mice. In this study, we investigated the efficacy of murine VEGFR2-specific CAR-T cells against syngeneic experimental gliomas and assessed the CAR-T cell infiltration of this approach. METHODS VEGFR2-CAR-T cells were generated by retroviral transduction to express a second generation CAR construct. Their activity was assessed in co-culture assays in vitro against murine endothelial and glioma cells, respectively. Syngeneic orthotopic mouse glioma models were used to explore the infiltration of intravenously administered CAR-T cells by in vivo fluorescence molecular tomography (FMT), ex vivo flow cytometry as well as ex vivo 3D light-sheet fluorescence microscopy (LSFM). RESULTS VEGFR2-CAR-T cells showed anti-endothelial and anti-glioma activity in vitro. Intravenous treatment with fluorescently labeled CAR-T or mock-transduced T cells of tumor-bearing mice resulted in a higher FMT signal at the tumor site. This was confirmed by ex vivo flow cytometry, wherein CAR-T cells represented a larger fraction of all T cells within the tumor (26.5% CAR versus 5.4% Mock, p = 0.0013) resulting in a higher donor T cell to tumor cell ratio. Similarly, significantly more VEGFR2-CAR-T cells were detected at the tumor site compared to tumor-targeting (but not vessel-targeting) control CAR-T cells. Currently, VEGFR2-CAR-T cell infiltration patterns as well as vasculature density are further investigated and visualized by LSFM. CONCLUSION VEGFR2-CAR-T cells show improved glioma infiltration in syngeneic mouse models. Therefore, VEGFR2 might be a relevant target that could improve CAR-T cell infiltration in glioblastoma.
RTID-06. THE PIVOTAL METIS (EF-25) STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC) FOLLOWING RADIOSURGERY
Authors: Minesh Mehta, Paul Brown, Maciej Harat, David Roberge, Manmeet Ahluwalia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: TTFields are electric fields that disrupt processes necessary for cancer cell survival and can stimulate an antitumor immune response in preclinical NSCLC models. TTFields therapy is a noninvasive and locoregional treatment approved for glioblastoma, which has recently demonstrated a survival benefit when applied to the thorax with standard of care (SOC) systemic therapy in patients with metastatic NSCLC that progressed on/after platinum. Here we describe the pivotal METIS study (EF-25, NCT02831959) evaluating the efficacy and safety of TTFields therapy applied to brain metastases from NSCLC. TRIAL DESIGN: Patients (270) with 1–10 brain metastases from NSCLC will receive stereotactic radiosurgery (SRS), followed by 1:1 randomization to TTFields (NovoTTF-200M [150 kHz] applied to the head ≥ 18 h/day) with best SOC, or best SOC alone. Key inclusion criteria are life expectancy ≥ 3 months, a new diagnosis of 1 inoperable or 2–10 supra and/or infratentorial brain metastases from NSCLC, that are amenable to SRS. Patients who had prior whole brain radiotherapy, or have single operable, leptomeningeal, or recurrent brain metastases, certain genetic mutations, or severe comorbidities or contraindications, are not eligible. The primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate, time to second intracranial progression, time to first/second intracranial progression by modified RECIST v1.1, rate of intracranial progression, time to distant progression, rate of cognitive decline, quality of life, neurocognitive failure-free survival, and safety. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee reviewed the study data and recommended continuation. The study includes 128 sites in Europe, Israel, mainland China, North America, and Hong Kong. The final patient was enrolled in March 2023.